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Production capacity Production capacity and supply of and supply of typhoid fever typhoid fever vaccinesvaccines
for developing for developing countriescountries
Rodney Carbis
Head Vaccine Development, IVI
Licensed Typhoid Fever VaccinesLicensed Typhoid Fever Vaccines
Anti-typhoid vaccination in theUnited States Army, c. 1915.
Soldiers in a hospital on the Civil War battlefield, Georgia,scene of the Army’s worst typhoid epidemic in 1898.
Licensed Typhoid Fever VaccinesLicensed Typhoid Fever Vaccines
1. Vi polysaccharide vaccineLicensed for use in persons
> 2 years of age
2. Live attenuated oral Ty21aLicensed in persons 5 years of age and above.
3. Heat-inactivated phenol preserved
• Very reactogenic due to LPS
• Still licensed and used in some countries
N-acetyl-αααα-D-galactosaminuronic acid
n = 2,000 – 10,000
Future vaccinesFuture vaccines
Vi conjugateVi conjugateDr John Robbins NIHDr John Robbins NIH
NHNHCO(CH2)4CONHNH
Exoprotein A (rEPA)
SpacerC=O
C=O
Vi
Capsular Polysaccharide
Vi conjugate vaccineVi conjugate vaccineClinical trialsClinical trials
•• In phase II trials high seroconversion rates In phase II trials high seroconversion rates after one dose and clear booster responses after one dose and clear booster responses following the second dose.following the second dose.
•• Randomized controlled phase III trial in Randomized controlled phase III trial in Vietnam in children (2 Vietnam in children (2 –– 5 years old).5 years old).
•• 2 injections 6 weeks apart2 injections 6 weeks apart•• 92% protection after 27 months92% protection after 27 months(active surveillance)(active surveillance)
Future vaccinesFuture vaccines
Live attenuated candidates
1.1. CVD 908CVD 908--htrAhtrA with a mutation with a mutation deletion in the deletion in the htrAhtrA genegene–– CDV 909 derived from 908 but CDV 909 derived from 908 but
Vi positive (ACAMBIS/BERNA)Vi positive (ACAMBIS/BERNA)
2.2. χχ4073 strain with a triple 4073 strain with a triple mutation deletion in the mutation deletion in the cyacya, , crpcrp, and , and cdtcdt genes (Roy Curtis)genes (Roy Curtis)
3.3. Ty800 with a double mutation Ty800 with a double mutation deletion in deletion in phoPphoP and and phoQphoQ(AVANT)(AVANT)
4.4. ZH9 a double mutation in ZH9 a double mutation in aroCaroCand and ssaVssaV genes (EMERGENT)genes (EMERGENT)
Live attenuated Ty21aLive attenuated Ty21a
Derived from Ty2• Developed in the early 1970s
• Non specific mutagenesis using nitrosoguanidine
• A large number of mutations including galE gene and other genes responsible for the production of Vi
Live attenuated Ty21aLive attenuated Ty21a
Clinical trialsClinical trials
Phase III trials in Egypt and Chile and IndonesiaPhase III trials in Egypt and Chile and Indonesia
•• Three doses of Three doses of enteric coated capsulesenteric coated capsules provided 67% provided 67% protection over 3 years and 62% over 7 years.protection over 3 years and 62% over 7 years.
•• Three doses of Three doses of liquid formulationliquid formulation provided 77% provided 77% protection over 7 years.protection over 7 years.
•• The vaccine induced antiThe vaccine induced anti--Salmonella antibodies (O Salmonella antibodies (O antigen) and a strong cellantigen) and a strong cell--mediated immune response.mediated immune response.
Live attenuated Ty21aLive attenuated Ty21a
Vivotif formulation
Contains (2 to 6) x 109 cfu of Ty21a
(5 to 50) x 109 non viable Ty21a
– 26 to 130 mg sucrose
– 1 to 5 mg ascorbic acid
– 1.4 to 7.0 mg amino acid mixture
– 100 to 180 mg lactose
– 3.6 to 4.4 mg magnesium stearate
Live attenuated Ty21aLive attenuated Ty21a
Licensed in 56 countries
Produced by Berna Biotech – Switzerland– Presented as phtallate-coated gelatin capsules
– A liquid formulation is also available (with sachet and buffer)
– Administered as three doses 2 days apart
Vi capsular polysaccharide vaccineVi capsular polysaccharide vaccine
Licensed in more than 92 countriesLicensed in more than 92 countries
Producers includeProducers include–– SanofiSanofi Pasteur Pasteur –– TyphimTyphim ViVi–– GlaxoSmithKline GlaxoSmithKline –– TypherixTypherix–– Bharat Biotech India Bharat Biotech India -- TyphbarTyphbar ViVi–– Bio Med India Bio Med India –– TyphoTypho ViVi–– Finlay Institute Cuba Finlay Institute Cuba –– VaxVax--TyViTyVi–– IVAC VietnamIVAC Vietnam–– 6 producers in China including6 producers in China including
•• Lanzhou InstituteLanzhou Institute•• Chengdu InstituteChengdu Institute
Vi capsular polysaccharide vaccineVi capsular polysaccharide vaccine
Clinical trials• Single subcutaneous or intramuscular dose of 25µµµµg of
purified Vi polysaccharide• Randomized controlled trials
– 72% protection 17 months post vaccination in Nepal– 65% protection 21 months post vaccination in South Africa– Studies in China using locally made vaccine show similar results
• Vi polysaccharide is a T-cell independent antigen and as such is poorly immunogenic in infants
• Antibody responses are not boosted by additional doses
Features of Vi vaccineFeatures of Vi vaccineSuitability for public healthSuitability for public health
Single dose
Highly temperature stablePhysicochemical characteristics unchanged after 6 months at 37oC
Production technology relatively simple
High yields - No supply problems
Affordable to public health programsPublic sector purchases for less than 50 cents per dose
Large number of manufacturesCompetition keeps price affordable for public sector purchases
Vi capsular polysaccharide vaccineVi capsular polysaccharide vaccine
Fermentation
Vi CapsularPolysaccharide
Purification
Inactivation
SterileFiltration
Formulation
Estimates of yieldEstimates of yield
Final yield 100mg/litre of fermentation broth.
Equivalent to 4,000 doses per litre.
1000 litre fermentation 4,000,000 doses
Typhoid fever vaccinationTyphoid fever vaccination
• The WHO recommends that the immunization of school aged children be undertaken wherever the control of the Typhoid fever is a priority.
Cost of vaccinesCost of vaccines
Pakistan:Sanofi, GSK, and Berna all market
vaccine with annual sales of approximately 70,000 doses at USD 6.00 per dose.
India:Vaccine is produced at well under
USD 1.00 per dose. Large numbers of doses are being sold in India but all to the private market.
Typhoid Vaccine Market ShareTyphoid Vaccine Market Share
SanofiSanofi46%46%
Local manufacturers Local manufacturers 42%42%
Berna
Berna
5%5%GSK
GSK
7%7%
60 million doses per annum60 million doses per annum
Current vaccinationCurrent vaccination
Both currently licensed vaccines have good safety profiles and have shown reasonable protective efficacy.
Neither has been widely adopted as a routine public health tool in developing countries with endemic typhoid fever
Population statisticsPopulation statistics
200,000,000School aged children (6 -12 years)
47,290,0004,729,000155,000,000Pakistan
45,000,0004,500,000220,000,000Indonesia
260,000,00026,000,0001,087,000,000India
Approximate no. of children
< 12
Annual no. of births
Population
2004Country
Developing Country ProducersDeveloping Country ProducersCould produce and market vaccine at affordable pricesCould produce and market vaccine at affordable prices
Developing a Vi vaccineBioFarma
Indonesia
Producer supplying Vietnamese market
IVAC
Vietnam
StatusCompany
Several producers mainly supplying private market in China
Chinese Producers
Developing a Vi vaccineShantha
India
Producer and selling in IndiaBioMed
India
Producing and distributing vaccine
Licensed in several countries
Bharat Biotech
India
Age distribution of typhoid Fever cases identified at a diagnostic referral center in Dhaka, Bangladesh (n=391)
1008.4> 20 yr
91.613.010~19 yr
78.524.05~9 yr
54.512.337~48 mo
42.215.325~36 mo
26.917.413~24 mo
9.58.76~12 mo
0.80.80~5 mo
Cumulative (%)% of IsolatesAge
Saha, Baqui, Hanif, Darmsladt, Ruhulamin, Nagatake, Santosham, and Black Pediatr. Infect Dis J. 2001:21;521-4
Age distributionAge distribution
Incidence of Culture-Confirmed Typhoid Fever
573
340
149
24 29
413
494
180
0
100
200
300
400
500
600
700
Karachi Kolkata North Jakarta Hue Hechi
Incidence per 100,000
2-4 5-15
DOMI ResultsDOMI Results
Conjugate vaccine introductionConjugate vaccine introduction
• Justification for a Vi conjugate vaccine– Vaccination of children <2 years of age– Better responses in 3 - 5 years olds (and older children)
compared with Vi polysaccharide vaccine– Vaccination with other EPI vaccines
• Will take up to 7 years to license• Meanwhile 21 million cases of typhoid fever resulting
in excess of 200,000 plus deaths• Vi production and capacity must be established
before conjugate can be produced• It makes sense to establish a public sector market
with Vi now and introduce Vi-conjugate when it becomes licensed
Vi conjugate development at IVIVi conjugate development at IVI
NHNHCO(CH2)4CONHNH
Spacer
C=O
O=C
Vi
Diphtheria toxoid
Dr Clark Cui at IVI
Technology assistance from NIH